There are a large number of conditions in which anti-oxidant activity has been implicated as being useful in the development of treatment regimes. These include acute conditions such as myocardial ischaemia, stroke, cardiac surgery (e.g. coronary bypass surgery), and chronic conditions such as diabetes, atherosclerosis and hypertension. Notwithstanding the prevalence of disorders of this type there is still the need to develop new drugs that can be used in the treatment of these conditions.
For example one of the best known of the conditions of this type, cardiovascular disease (CVD), is currently the leading cause of mortality worldwide in adults aged 60 years and above. While there are various types of CVD, the two most common causes of fatality are coronary heart disease and stroke. In 2002, the total number of deaths from CVD globally amounted to 16.7 million, of which approximately 7 million resulted from coronary heart disease and a further 6 million from stroke. In Australia, CVD is also the leading cause of death where 38% of all deaths in 2002 were a result of CVD. In addition, CVD causes long-term disability in 1.10 million Australians. Consequently, CVD represents a heavy economic burden with the direct costs of the disease estimated to be approximately $5.4 billion in 2000-1 in Australia, and $286 billion in 1999 in the United States of America, and it is predicted that this figure will continue to rise due to the aging population. Although CVD has long been thought to be a disease predominantly occurring in developed countries, it has become increasingly clear that it is also emerging in third-world countries and is already the leading cause of mortality in some regions of the developing world. As such, there is an urgent need to develop novel agents for the treatment or prevention of CVD.
The underlying cause of CVD is atherosclerosis, which is the development of fatty deposits on normally-smooth blood vessels, which start to form in people from a very young age. There are a number of risk factors such as obesity, high blood cholesterol and high blood pressure that predispose individuals to the formation of these fatty deposits, which in turn places them in a high risk category for CVD. As the fatty deposits continue to develop, the vessel narrows and the wall thickens, hardens and loses elasticity. Blood flow through these vessels is disturbed resulting in platelet activation, causing the formation of a thrombus at the site of the lesion, which occludes the vessel. When this occurs in the heart or brain, ischaemic heart disease or stroke, respectively, result.
Oxygen supply may be restored after ischaemic injury, by dislodging or dissolving the thrombus. However, paradoxically, restoration of the oxygen supply can lead to a worsened secondary condition known as reperfusion injury. The reintroduction of oxygen causes the production of reactive oxygen species (ROS), which exacerbates and accelerates the injury already produced by the ischaemia. ROS include free radicals that have an unpaired electron, such as O2. and HO., as well as other reactive species such as H2O2. HO. is particularly reactive and reacts indiscriminately with membrane lipids, proteins and DNA, degrading them and causing cellular damage. There are various sources of ROS, including nitric oxide synthase, myeloperoxidase, superoxide dismutase, mitochondrial electron transport, metabolism of arachidonic acid by cyclooxygenase and xanthine oxidase. One of the pathways for production of ROS is shown below.

A diet high in cholesterol has long been known to be associated with CVD. Epidemiological studies have indicated that the French population has a lower than predicted incidence of CVD given their comparatively high fat diet. This anomaly is known as “The French Paradox” (9-11). With other risk factors for CVD, such as smoking and obesity, comparable to other Western populations, it has been suggested that the regular consumption of red wine in the French diet holds the key to cardio-protection. Later studies have suggested that it is a non-alcoholic component of wine, the flavonoids, that contribute to protective effects in the cardiovascular system. In other studies, flavonoids have been found to possess many beneficial properties, such as anti-inflammatory, anti-allergic, anti-viral, anti-thrombotic and anti-carcinogenic effects.
Flavonoids are polyphenolic compounds with many subclasses, and previous studies have shown a group of compounds called flavonols to be of particular interest for treatment of and protection against CVD. Flavonols possess 3 rings, with a hydroxyl group in the 3-position of the C ring. They are found in a large variety of plant materials, such as fruits, vegetables, nuts, seeds, herbs, spices, stems, flowers, tea and red wine, and have been consumed by humans since prehistoric times, suggesting that they are unlikely to possess significant adverse effects. Some structure-activity relationship studies have been performed to identify substituents on the flavonol ring system that are important for vasorelaxant and antioxidant activity. It has been found that the 3-OH group of the C ring was essential for endothelium-dependent vasorelaxant activity and additional hydroxyl groups at the 3′ and 4′ positions of the B ring further improves biological activity. For antioxidant activity, the 3-OH of the C ring, attached to the C2-C3 double bond, which is in conjugation with the 4-oxo group of the C ring, together with either a 4′-hydroxy or a 3′,4′-catechol moiety on the B ring were shown to be important. Thus, the most potent flavonol for antioxidant and vasorelaxant activities described to date is 3′,4′-dihydroxyflavonol (diOHF).

There is significant potential for flavonols or flavonol analogues to be useful in the treatment of conditions which can be treated by anti-oxidants due to the strong anti-oxidant activity demonstrated by compounds of this general structural type. Unfortunately, however, there are a number of problems encountered for compounds of this general structural type that lead to a reduction in their ability to be used in this way. For example one undesirable property of compounds of this type is that they are generally insoluble in water making their use as drugs impractical. In addition many of these compounds display multiple biological activities, which in many instances is undesirable and limits their broad spectrum use. For example many of the flavonols display both anti-oxidant and vasodilatory activity. This is generally undesirable as it is preferable to be able to administer a drug with a single activity in order to limit the possible adverse side effects. In relation to flavonols which have both anti-oxidant and vasodilatory activity there are a number of instances in which such dual activity is undesirable. If the anti-oxidant activity is the desired end result then vasodilatory activity may lead to adverse side effects such as hypotension (excessively low blood pressure), postural hypotension (dizziness and possible collapse when moving from lying to standing), tachycardia (an excessively high heart rate to try to compensate for the low blood pressure) and arrhythmias. As such the fact that flavonols have both properties is undesirable. It would therefore be desirable to develop flavonols with improved specificity as current flavonols do not possess any selectivity of note.
It would therefore be desirable to overcome or ameliorate one or more of the observed problems with the flavonol compounds as discussed above.
The present invention is based on the finding by the present applicants that modification of flavonols or flavonol compounds in certain pre-defined ways leads to improvements in the functional performance of the compounds and addresses one or more of the deficiencies identified above.